Unsaturated ketones

ABSTRACT

This invention relates to a process for the preparation of 2-alkenyl-4-hydroxy-3-methyl-2-cyclopenten-1-ones from the reaction product of 2,4-pentane dione and a 2-propen-or 2-propyn-1-ol derivative including intermediates therein.

This is a division of application Ser. No. 547,688 filed Feb. 6, 1975,now U.S. Pat. No. 3,935,440, which in turn is a divisional applicationof Ser. No. 158,080 filed June 29, 1971, now U.S. Pat. No. 3,884,970.

BACKGROUND OF THE INVENTION

The class of compounds commonly referred to as pyrethrins is generallyunderstood to include the four major active ingredients of pyrethrumviz. Pyrethrin I, Cinerin I, Pyrethrin II and Cinerin II. Pyrethrum isthe commercial extract of the herbaceous perrennial Chrysanthemumcinerariaefolium and is an important source of natural insecticides. Thepyrethrins which, as noted above, comprise the major insecticidalconstituents of pyrethrum and are especially useful insecticides byvirtue of their increased insecticidal potency when used with knownsynergists, e.g., piperonyl butoxide, their low mammalian toxicity,rapid knockdown or paralytic properties, and the absence of inducedinsect resistance from exposure to sublethal doses.

Owing to their importance, the preparation of pyrethrins has been thesubject of much investigation. There are, however, no commerciallyacceptable syntheses available for the preparation of the pyrethrins andthe entire commercial production of pyrethrins is accomplished byextraction from pyrethrum flowers. Such commercial extraction proceduresinvolve treatment with organic solvents which invariably results in theextraction of substantial amounts of inactive and undesirable impuritiesnecessitating costly and cumbersome purifications in order to obtaininsecticidally useful pyrethrins. The novel process of this inventionprovides a method for the synthesis of several of the pyrethrins andpyrethrin analogs via easily accessible starting materials.

DETAILED DESCRIPTION OF THE INVENTION

This invention pertains to a novel chemical synthesis of a2-alkenyl-4-hydroxy-3-methyl-2-cyclopenten-1-one of the formula:##STR1## wherein R is hydrogen, lower alkyl or lower alkenyl.

The compound of formula I can be prepared from the reaction of2,4-pentadione and a 2-propen- or 2-propyn-1-ol derivative of theformula:

    HO--CH.sub.2 -- C C--R                                     II

wherein R is as above and the dotted bond can be optionally hydrogenatedby the following reaction scheme: ##STR2## wherein R is as above; X is ahalogen; R₂ is lower alkyl and the dotted bond can be optionallyhydrogenated.

In reacting the compound of formula II with the compound of formula IIIto produce a compound of the formula IV via reaction step (a), thehydroxy group on the compound of formula II is converted to a leavinggroup. This is accomplished by reacting the hydroxy group on thecompound of formula II with an acid halide to form a leaving group. Theacid halides suitable for forming leaving groups are the halides oforganic sulfonic acids such as p-toluene sulfonic acid and lower alkylsulfonic acid.

Especially preferred as the leaving group in the 11-position is thep-toluene sulfonyloxy group such as tosyloxy, lower alkyl sulfonyloxy,such as mesyloxy.

The compound of formula II containing a leaving group is reacted withthe compound of formula III in the presence of a base. Any conventionalbase can be utilized in carrying out this reaction. Among the preferredbases which can be utilized are the tertiary amine bases such as thetri(lower alkyl)amines, heterocyclic amine bases such as pyridine, etc.Among the tertiary amine bases, compounds such as N,N-diisopropyl ethylamine, triethyl amine, trimethylamine, etc. are generally preferred. Incarrying out this reaction, temperature and pressure are not criticaland this reaction can be carried out at room temperature and atmosphericpressure. Generally, it is preferred to utilize temperatures of fromabout -30° C. to 30° C. Generally, this reaction is carried out in thepresence of an aqueous reaction medium containing a water miscibleorganic solvent. Any conventional water miscible organic solvent such asthe lower alkanols can be utilized. Among the organic solvents, methanolis preferred.

In the reaction of step (a), the compound of formula IV can be isolatedfrom the reaction medium by means of a chelating agent. Any conventionalchelating agent such as cupric acetate monohydrate can be utilized toisolate the compound of formula IV in pure form from its reactionmedium. The chelate can be converted to the compound of formula IV bytreatment with a mineral acid such as sulfuric acid. Any conventionalmeans for regenerating the components of a chelate can be utilized incarrying out this reaction.

The compound of formula IV is converted to the compound of formula V,via reaction step (b) by treating the compound of formula IV with acompound of the formula: ##STR3## wherein R₂ is as above. Generally,this reaction is carried out by heating the reaction to temperaturebelow 65° C. Any inert organic solvent can be utilized in the reactionmedium. Solvents such as lower alkanols, aromatic hydrocarbons such asbenzene, etc. can be utilized. When a lower alkanol is utilized as thesolvent, this lower alkanol should be an alcohol having the formula: R₂OH wherein R₂ is the same alkyl group as in the compound of formula X.Generally, this reaction is carried out in the presence of an acidcatalyst. Any conventional acid catalyst can be utilized. Generally, itis preferred to utilize p-toluene sulfonic acid as the acid catalyst.The reaction of step (b) is carried out by distilling the reactionmedium at a temperature of below 65° C. Generally, it is preferred todistill the reaction mixture at temperatures of from 40° C. to 65° C.

The compound of formula VI is converted to the compound of formula VIIvia reaction step (d) by treating the compound of formula VI with alower alkyl lithium and a methylene halide. Among the preferred alkyllithiums for carrying out this reaction is n-butyl lithium. Among thepreferred methylene halides for carrying out this reaction is methylenechloride. Generally, this reaction is carried out at a temperature offrom -70° C. to -100° C. This low temperature can be maintained byutilizing a liquid nitrogen atmosphere. In carrying out this reaction,any conventional inert organic solvent having a freezing point of lowerthan -70° C. can be utilized. Among the preferred solvents are the ethersolvents such as tetrahydrofuran and diethyl ether.

The compound of formula VII can be converted to the compound of formulaVIII via reaction step (e). This reaction can be carried out by treatingthe compound of formula VII with a mineral acid, preferably a dilutemineral acid such as 10% by weight aqueous hydrochloric acid. Anyconventional mineral acid can be utilized in carrying out this reaction.Generally, this reaction is carried out in a solvent medium containingwater. This solvent medium can contain an inert water miscible organicsolvent. Any conventional inert water miscible organic solvent can beutilized in carrying out this reaction. Among the preferred solvents arethe ether solvents such as dioxane, tetrahydrofuran, etc. In carryingout this reaction temperature and pressure are not critical and roomtemperature and atmospheric pressure can be utilized.

The compound of formula VIII can be converted to the compound of formulaI-A via reaction step (f) by treating the compound of formula VIII witha base. Any conventional base can be utilized in carrying out thisinvention. Among the conventional bases are included the alkali metalhydroxides such as sodium hydroxide, potassium hydroxide, etc.; thealkaline earth metal hydroxides such as calcium hydroxide, bariumhydroxide, etc. Generally, this reaction is carried out in an aqueousmedium. If desired, a water miscible organic solvent can be present inthe reaction medium. Among the water miscible organic solvents which canbe present, the lower alkanols such as methanol are preferred. Incarrying out this reaction, temperature and pressure are not criticaland this reaction can be carried out at room temperature and atmosphericpressure. On the other hand, elevated or reduced temperatures can beutilized. Generally, it is preferred to carry out this reaction at atemperature of from 0° C. to 70° C.

In accordance with this invention, the compounds of formula II, IV, V,VI, VII, VIII and I-A, where the dotted bond is not hydrogenated, can bereduced by partial hydrogenation to the olefinic double bond at anystage of the process. Any conventional method of partial hydrogenationcan be utilized in carrying out this reaction. For example, thesecompounds can be catalytically hydrogenated in an inert solvent such asethyl acetate, toluene or petroleum ether in the presence of a selectivehydrogenation catalyst, e.g., a palladium-lead catalyst in the presenceof quinoline of the type disclosed in Helv. Chim. Acta, 35, 446 (1952).

In accordance with this invention, it is generally preferred topartially hydrogenate the acetylenic compounds of formula V, VI, VII,VIII and I-A. It has been found that the use of a selectivehydrogenation catalyst such as palladium deactivated with lead producesa cis configuration across the resulting double bond. Therefore, by useof 2-propyn-1-ol of the formula II, the above process provides a meansfor stereo-specifically producing pyrethrins.

Utilizing the process of this invention, one can convert 2-butyn-1-ol to2-(but-2-enyl)-3-methyl-4-hydroxy-2-cyclopenten-1-one (Cinerolone);2-propyn-1-ol to 2-allyl-3-methyl-4-hydroxy-2-cyclcopenten-1-one(allethrolone); 3-pentyn-1-ol to2-(pent-2-enyl)-3-methyl-4-hydroxy-2-cyclopent-1-one (jasmolone); and1,3-pentadien-5-ol to2-(2,4-pentadienyl)-3-methyl-4-hydroxy-2-cyclopenten-1-one.

Conversion of the 2-alkenyl-3-methyl-4-hydroxy-2-cyclopenten-1-one,products of formula I to the insecticidally useful pyrethrins andpyrethrin analogs is readily accomplished by esterification withappropriate cyclopropane carboxylic acid, e.g., chrysanthemummonocarboxylic acid (chrysanthemic acid), pyrethric acid and the like,which are known in the art. The preparation of pyrethrins and pyrethrinanalogs by esterification of substituted3-methyl-4-hydroxy-2-cyclopenten-1-ones with cyclopropane carboxylicacid has been described, for example, by, among others, L. Crombie etal., J.C.S. p. 3963 (1956); L. Crombie et al., J.C.S. p. 1152 (1950) andSchecter et al., J.A.C.S. 71, 3165 (1949).

As used throughout the instant specification, the term halogendesignates all four halogens, i.e., chlorine, bromine, iodine, andfluorine, with chlorine being preferred. The term "lower alkyl"designates lower alkyl groups containing from 1 to 7 carbons such asmethyl, ethyl, propyl, 1-propyl, etc. The term "lower alkenyl"comprehends lower alkenyl groups containing from 2 to 7 carbon atomssuch as vinyl, allyl, etc.

The invention will be more fully understood from the specific exampleswhich follow. These examples are intended to be illustrative of theinvention, and are not to be construed as limitative thereof. Thetemperatures in these examples are in degrees centigrade and the etherutilized is diethyl ether.

EXAMPLE 1 Preparation of 3-acetyl-5-heptyn-2-one

A solution of 75.0 g. (0.75 mol.) of 2,4-pentanedione, 113 g. (0.50mol.) 2-butyl-p-toluenesulfonate and 97.0 g. (0.75 mol.) ofN,N-diisopropyl ethyl amine in 100 ml. of water and 150 ml. of methanolwas briefly stirred at 0° and then at room temperature for 24 hours,cooled in an ice bath, made just acidic with dilute hydrochloric acid,diluted with water (300 ml.) and extracted with diethyl ether (4× 200ml.). The combined ethereal extracts were washed with 200 ml. each ofwater and saturated aqueous sodium chloride, dried (MgSO₄),concentrated, and distilled under reduced pressure to remove excess2,4-pentanedione. To the residue dissolved in 100 ml. of methanol wasadded a hot filtered solution of 50 g. (0.25 mol.) of cupric acetatemonohydrate in 375 ml. of water. After being cooled overnight in arefrigerator, the suspension was filtered and washed with methanol anddiethyl ether to give 3-acetyl-5-heptyn-2 -one as a gray copper salt.The salt was stirred vigorously with 500 ml. of 20% aqueous sulfuricacid and 400 ml. of diethyl ether until consumed, the ether layerremoved and the blue aqueous phase extracted with ether (3× 200 ml.).The combined ethereal layer and extracts were washed with 200 ml. eachof water and saturated aqueous sodium chloride, dried (MgSO₄), andconcentrated to afford 3-acetyl-5-heptyn-2-one as a yellow oil.Distillation gave a pale yellow oil; B.P. 85° . (2.6 mmHg).

EXAMPLE 2 Preparation of 2-methoxy-3-acetyl-1-hepten-5-yne

A solution of 38.0 g. (0.25 mol.) of 3-acetyl-5-heptyn-2-one, 32.3 g.(0.31 mol.) of 2,2-dimethoxy-propane, and 5 mg. of p-toluenesulfonicacid in 25 ml. of absolute methanol and 25 ml. of benzene was slowlydistilled until the material boiling below 65° had been removed, thenstirred with 1 g. of sodium carbonate and filtered to produce2,2-dimethoxy-3-acetyl-5-heptyne in the filtrate.

Distillation of the filtrate afforded 25.9 g. of a pale yellow oil, b.p.77°-82° (2.0 mmHg). The distillate was dissolved in 100 ml. of ether,washed with ice-cold 2% by weight aqueous sodium hydroxide (3× 35 ml.),water, and saturated aqueous sodium chloride, dried (Na₂ SO₄),concentrated and distilled to yield 2-methoxy-3-acetyl-1-hepten-5-yne;b.p. 81°-83° (2.0 mmHg).

EXAMPLE 3 Preparation of (Z)-2-methoxy-3-acetyl-1,5-heptadiene

A mixture of 9.96 g. (60 mmol.) of 2-methoxy-3-acetyl-1-hepten-5-yne,0.50 g. of Lindlar catalyst, and 10 drops of synthetic quinoline in 100ml. of ethyl acetate was stirred under one atmosphere of hydrogen untilhydrogen absorption was complete, then filtered, concentrated anddistilled to afford (Z)-2-methoxy-3-acetyl-1,5-heptadiene; b.p. 64°-66°,(2.0 mmHg).

EXAMPLE 4 Preparation of(Z)-1-chloro-1,2-epoxy-2-methyl-3-(1-methoxyethenyl)-5-heptene

A solution of 28 ml. (45 mmol.) of 1.6 M n-butyl lithium in hexane wasadded dropwise and with stirring during 45 minutes to a solution of 3.2ml. (50 mmol.) of methylene chloride in 20 ml. of diethyl ether, 20 ml.of petroleum ether, and 140 ml. tetrahydrofuran under nitrogen cooled to-95° in a toluene-liquid nitrogen slush. After 30 minutes, a solution of6.72 g. (40 mmol.) of (Z)-2-methoxy- 3-acetyl-1,5-heptadiene in 60 ml.of tetrahydrofuran was added dropwise during 45 minutes and the mixturewas allowed to warm slowly to room temperature and then allowed toreflux for three hours. The mixture was then cooled, concentrated,poured into 200 ml. of saturated aqueous ammonium chloride, extractedwith diethyl ether, the combined ethereal extracts washed with saturatedaqueous sodium chloride, dried (Na₂ SO₄) and concentrated to afford (Z)-1-chloro-1,2-epoxy-2-methyl-3-(1-methoxyethenyl)-5-heptene.

EXAMPLE 5 Preparation of(Z)-1-chloro-1,2-epoxy-2-methyl-3-acetyl-5-heptene

A solution of 6.75 g. (31.5 mmol.) of crude(Z)-1-chloro-1,2-epoxy-2-methyl-3-(1-methoxy-ethenyl)-5-heptene in 350ml. of 2:1 tetrahydrofuran: 10% by weight aqueous hydrochloric acid wasstirred at room temperature for 30 minutes, concentrated, extracted withdiethyl ether, the ethereal extracts washed with water and saturatedaqueous sodium chloride, dried (Na₂ SO₄) and concentrated to afford(Z)-1-chloro-1,2-epoxy-2-methyl-3-acetyl-5-heptene as a yellow oil.

EXAMPLE 6 Preparation of (±)cis-Cinerolone

A solution of 4.15 g. (20 mol) of crude(Z)-chloro-1,2-epoxy-2-methyl-3-acetyl-5-heptene and 6.30 g. (20 mol.)of barium hydroxide octahydrate in 200 ml. of 50% aqueous methanol wasstirred at room temperature under argon for 1 hour, neutralized withdilute hydrochloric acid, concentrated, extracted with ether, theextract washed with water and saturated aqueous sodium chloride, dried(Na₂ SO₄), concentrated and distilled to afford (±)cis-Cinerolone as anoil, b.p. 95°-100° (0.05 mmHg)

I claim:
 1. A compound of the formula: ##STR4## wherein R is hydrogen, lower alkenyl or lower alkyl; R₃ is lower alkyl, and the dotted bond can be optionally hydrogenated.
 2. The compound of claim 1 wherein said compound is 2-methoxy-3-acetyl-1-hepten-5-yne.
 3. The compound of claim 1 wherein said compound is 2-methoxy-3-acetyl-1,5-heptadiene. 